ABSTRACT The circuit mechanisms that cause dystonia are poorly understood. A prominent hypothesis is that dystonia is caused by aberrant plasticity within motor structures, especially cortical-basal ganglia circuits. The lack of a suitable animal model is a critical barrier to progress. Our preliminary data indicate that we have developed a strategy to generate the ?rst rodent model of human task speci?c dystonia by uniquely combining genetic and behavioral manipulations. This strategy is based on observations suggesting that dystonia requires ?two hits?: a genetic predisposition to abnormal plasticity and a plasticity-inducing environmental trigger (e.g., repetition of speci?c dexterous movements as with musician's dystonia). We modeled the genetic predisposition with our established model of DYT1 dystonia, caused by inherited mutation in the gene encoding torsinA. TorsinA mutant ?Dlx-CKO? mice do not show abnormal movements at baseline, but exhibit selective abnormalities of striatal cholinergic interneurons (ChIs), providing a substrate for striatal and perhaps downstream cortical dysfunction. Strikingly, Dlx-CKO mice trained to repetitively perform a dexterous paw reaching task develop abnormal, phasic, dystonic-like movements. In contrast, these mice do not develop abnormal movements after repetitively performing a non-dexterous rotarod task. This proposal will focus on establishing the validity and utility of this long-sought model of dystonia. We hypothesize that abnormal function of ChIs in the setting of repetitive dexterous limb movements causes 1) abnormal basal ganglia output reminiscent of deep brain recordings of human subjects with dystonia, and 2) task-specific dystonic-like movements in Dlx-CKO mice. We will test this hypothesis with three Speci?c Aims. In Aim 1, we will de?ne the necessary and suf?cient behavioral conditions for these mice to develop abnormal movements. In Aim 2, we will examine the electrophysiology of basal ganglia output nuclei as these movements develop, and compare them to recordings from human dystonia patients. In Aim 3, we will manipulate striatal cholinergic interneurons in Dlx-CKO and wild type mice to de?ne the speci?c role(s) of these neurons in generating abnormal movements. Successful completion of these Aims will establish a unique model of task speci?c dystonia with high construct, face and predictive validity. This model will exert a powerful impact on the dystonia community by allowing detailed study of network mechanisms in dystonia and suggesting novel therapeutic approaches. More generally, this model will improve understanding of normal interactions between extrapyramidal and pyramidal motor systems, with broad relevance for a range of movement disorders.